Kinomic profiling of tumour xenografts derived from patients with non-small cell lung cancer confirms their fidelity and reveals potentially actionable pathways.

TitleKinomic profiling of tumour xenografts derived from patients with non-small cell lung cancer confirms their fidelity and reveals potentially actionable pathways.
Publication TypeJournal Article
Year of Publication2021
AuthorsTabbo F, Guerrera F, van den Berg A, Gaudiano M, Maletta F, Bessone L, Nottegar A, Costardi L, de Wijn R, Ruijtenbeek R, Delsedime L, Sapino A, Ruffini E, Hilhorst R, Inghirami G
JournalEur J Cancer
Volume144
Pagination17-30
Date Published2021 02
ISSN1879-0852
KeywordsAged, Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred NOD, Mice, SCID, Prognosis, Protein Kinase Inhibitors, Protein Kinases, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Abstract

INTRODUCTION: High fidelity between non-small cell lung cancer (NSCLC) primary tumours and patient-derived tumour xenografts (PDTXs) is of paramount relevance to spur their application. Extensive proteomic and kinomic analysis of these preclinical models are missing and may inform about their functional status, in terms of phosphopeptides and hyperactive signalling pathways.

METHODS: We investigated tumour xenografts derived from patients with NSCLC to identify hyperactive signalling pathways. Fresh tumour fragments from 81 NSCLC surgical samples were implanted in Nod/Scid/Gamma mice, and engrafted tumours were compared with primary specimens by morphology, immunohistochemistry, gene mutation analyses, and kinase activity profiling. Four different tyrosine and serine/threonine kinase inhibitors were tested against primary tumour and PDTX lysates using the PamGene peptide microarray platform.

RESULTS: The engraftment rate was 33%, with successful engraftment being more associated with poor clinical outcomes. Genomic profiles led to the recognition of hotspot mutations, some of which were initially undetected in donor samples. Kinomic analyses showed that characteristics of primary tumours were retained in PDTXs, and tyrosine kinase inhibitors (TKIs) responses of individual PDTX lines were either expected, based on the genetic status, or alternatively defined suitable targets unpredictable by single-genome fingerprints.

CONCLUSIONS: Collectively, PDTXs mostly resembled their parental NSCLC. Combining genomic and kinomic analyses of tumour xenografts derived from patients with NSCLC, we identified patients' specific targetable pathways, confirming PDTXs as a preclinical tool for biomarker identification and therapeutic algorithm'' improvement.

DOI10.1016/j.ejca.2020.10.036
Alternate JournalEur J Cancer
PubMed ID33316635
Related Faculty: 
Giorgio Inghirami, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700